title: Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial.
abstract: BACKGROUND
  Ascorbic acid reduced the severity of neuropathy in transgenic mice overexpressing peripheral myelin protein 22 (PMP22), a model of Charcot-Marie-Tooth disease type 1A (CMT1A) associated with the PMP22 duplication. However, in three 1-year trials, ascorbic acid had no benefit in human beings. We did a multicentre 2-year trial to test the efficacy and tolerability of ascorbic acid in patients with CMT1A.
  
  
  METHODS
  Adult patients (aged 18-70 years) with symptomatic CMT1A were enrolled from nine centres in Italy and the UK, and were randomly assigned (1:1 ratio) to receive 1·5 g/day oral ascorbic acid or matching placebo for 24 months. The randomisation sequence was computer generated by block randomisation, stratified by centre and disease severity, and patients were allocated to treatment by telephone. The primary outcome was change in the CMT neuropathy score (CMTNS) at 24 months. Secondary outcomes were timed 10 m walk test, nine-hole peg test, overall neuropathy limitations scale, distal maximal voluntary isometric contraction, visual analogue scales for pain and fatigue, 36-item short-form questionnaire, and electrophysiological measurements. Patients, treating physicians, and physicians assessing outcome measures were masked to treatment allocation. Analysis of the primary outcome was done on all randomised patients who received at least one dose of study drug. This study is registered, numbers ISRCTN61074476 (CMT-TRAUK) and EudraCT 2006-000032-27 (CMT-TRIAAL).
  
  
  RESULTS
  We enrolled and randomly assigned 277 patients, of whom six (four assigned to receive ascorbic acid) withdrew consent before receiving treatment; 138 receiving ascorbic acid and 133 receiving placebo were eligible for analysis. Treatment was well tolerated: 241 of 271 patients (89% in each group) completed the study; 20 patients (nine receiving ascorbic acid) dropped out because of adverse events. Mean CMTNS at baseline with missing data imputed was 14·7 (SD 4·8) in the ascorbic acid group and 13·9 (4·2) in the placebo group. Mean worsening of CMTNS was 0·2 (SD 2·8, 95% CI -0·3 to 0·7) in the ascorbic acid group and 0·2 (2·7, -0·2 to 0·7) in the placebo group (mean difference 0·0, 95% CI -0·6 to 0·7; p=0·93). We recorded no differences between the groups for the secondary outcomes at 24 months. 21 serious adverse events occurred in 20 patients, eight in the ascorbic acid group and 13 in the placebo group.
  
  
  CONCLUSIONS
  Ascorbic acid supplementation had no significant effect on neuropathy compared with placebo after 2 years, suggesting that no evidence is available to support treatment with ascorbic acid in adults with CMT1A.
  
  
  BACKGROUND
  Telethon-UILDM and AIFA (Italian Medicines Agency) for CMT-TRIAAL, and Muscular Dystrophy Campaign for CMT-TRAUK.
authors.affiliation: Clinic of Central and Peripheral Degenerative Neuropathies Unit, Department of Clinical Neurosciences, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation, Carlo Besta Neurological Institute, Milan, Italy. davide.pareyson@istituto-besta.it
authors.forename: Davide
authors.initials: D
authors.lastname: Pareyson
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
authors.forename: Angelo
authors.initials: A
authors.lastname: Schenone
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Fabrizi
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cavallaro
authors.forename: Lucio
authors.initials: L
authors.lastname: Santoro
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Vita
authors.forename: Aldo
authors.initials: A
authors.lastname: Quattrone
authors.forename: Luca
authors.initials: L
authors.lastname: Padua
authors.forename: Franco
authors.initials: F
authors.lastname: Gemignani
authors.forename: Francesco
authors.initials: F
authors.lastname: Visioli
authors.forename: Matilde
authors.initials: M
authors.lastname: Laurà
authors.forename: Davide
authors.initials: D
authors.lastname: Radice
authors.forename: Daniela
authors.initials: D
authors.lastname: Calabrese
authors.forename: Richard A C
authors.initials: RA
authors.lastname: Hughes
authors.forename: Alessandra
authors.initials: A
authors.lastname: Solari
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000975:Antioxidants / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000627:therapeutic use*; D002607:Charcot-Marie-Tooth Disease / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D000975:Antioxidants; D001205:Ascorbic Acid